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To discover the best-in-class Bruton's Tyrosine Kinase (BTK) inhibitors, for th treatment of autoimmune disorders like cancer (B-Cell Lymphoma (BCL)) and rheumatoid arthritis (RA), in the present investigation, novel structural optimizations were carried out. Introduction of novel bicyclic amine linkers and aromatic backbone led to series of compounds 9a-h and 14a-u. Compound 14b was found to be potent, orally bioavailable, selective and irreversible BTK inhibitor. In vitro, 14b showed IC

Background Obesity and diabetes are major metabolic disorders that progress to severe morbidity and mortality. Neuroendocrine mechanisms controlling energy balance indicate that combination therapies are needed to sustain weight loss. Lorcaserin was one of the approved therapies for the treatment of obesity, which is recently withdrawn because a safety clinical trial, shows an increased occurrence of cancer. Coagonist of glucagon-like-peptide-1 (GLP-1) and glucagon receptors is a novel investigational therapy demonstrated to have both anti-obesity and anti-diabetic effect. Here, we investigated the effect of combination of lorcaserin and a GLP-1 and glucagon receptors coagonist in diet-induced obese (DIO) mice model. Methods The diet-induced obese C57BL/6J mice were used to assess acute and chronic effect of lorcaserin, coagonist of GLP-1and glucagon receptors and their combination on food intake, body weight, and biochemical parameters. Results In acute study, combination of lorcaserin and coagonist causes synergistic reductions in food intake and body weight. Repeated treatment of combination of lorcaserin and coagonist showed enhanced body weight loss over time, which is due to reduction in fat mass (subcutaneous, retroperitoneal, mesenteric and epididymal fat pad) compared to individual therapy. Also, suppression of locomotor activity seen with lorcaserin was not evident in combination with coagonist. No additive effect was observed in glucose tolerance (intraperitoneal glucose tolerance test or insulin tolerance test), serum lipids, hepatic lipids, and energy expenditure in combination group. Conclusion These data suggest that combination of lorcaserin and coagonist could be a better combination to induce body weight loss.

PI3Kδ is implicated in various inflammatory and autoimmune diseases. For the effective treatment of chronic immunological disorders such as rheumatoid arthritis, it is essential to develop isoform selective PI3Kδ inhibitors. Structure guided optimization of an imidazo-quinolinones based pan-PI3K/m-TOR inhibitor (Dactolisib) led to the discovery of a potent and orally bioavailable PI3Kδ isoform selective inhibitor (10h), with an improved efficacy in the animal models.

Background:Balanced coagonists of glucagon-like peptide-1 (GLP-1) and glucagon receptors are emerging therapies for the treatment of obesity and diabetes. Such coagonists also regulate lipid metabolism, independent of their body weight lowering effects. Many actions of the coagonists are partly mediated by fibroblast growth factor 21 (FGF21) signaling, with the major exception of bile homeostasis. Since thyroid hormone is an important regulator of bile homeostasis, we studied the involvement of thyroid hormone in coagonist-induced changes in lipid and bile metabolism.Methods:We evaluated the effect of a single dose of coagonist Aib2 C24 chimera2 at 150 to 10000 µg/kg on tetraiodothyronine (T4) and triiodothyronine (T3) in high-fat diet-induced obese (DIO) mice and chow-fed mice. Repeated dose treatment of coagonist (150 µg/kg, subcutaneously) was assessed in four mice models namely, on lipid and bile homeostasis in DIO mice, propylthiouracil (PTU)-treated DIO mice, methimazole (MTM)-treated DIO mice and choline-deficient, L-amino acid-defined, highfat diet (CDAHFD)-induced nonalcoholic steatohepatitis (NASH).Results:Single dose treatment of coagonist did not alter serum T3 and T4 in chow-fed mice and DIO mice. Coagonist treatment improved lipid metabolism and biliary cholesterol excretion. Chronic treatment of GLP-1 and glucagon coagonist did not alter serum T3 in hypothyroid DIO mice and CDAHFDinduced NASH. Coagonist increased serum T4 in DIO mice after 4 and 40 weeks of treatment, though no change in T4 levels was observed in hypothyroid mice or mice with NASH.Conclusion:Our data demonstrate that coagonist of GLP-1 and glucagon receptors does not modulate bile homeostasis via thyroid signaling.

Opioid receptor agonists are effective analgesic agents. Central activation of the mu and/or kappa opioid receptors (KOR) is associated with CNS side effects, which limits their effectiveness. Recent studies indicated that peripherally restricted, selective KOR agonists were potent analgesics and devoid of CNS-related side effects. To confirm this hypothesis, we designed a novel, potent, and peripherally restricted KOR-selective agonist, ZYKR1. The analgesic efficacy, brain penetration and safety of ZYKR1 were assessed in pre-clinical models. ZYKR1 showed KOR agonistic activity in the cAMP assay, with an EC

Bruton's tyrosine kinase (BTK) plays a central and pivotal role in controlling the pathways involved in the pathobiology of cancer, rheumatoid arthritis (RA), and other autoimmune disorders. ZYBT1 is a potent, irreversible, specific BTK inhibitor that inhibits the ibrutinib‐resistant C481S BTK with nanomolar potency. ZYBT1 is found to be a promising molecule to treat both cancer and RA. In the present report we profiled the molecule for in‐vitro, in‐vivo activity, and pharmacokinetic properties. ZYBT1 inhibits BTK and C481S BTK with an IC50 of 1 nmol/L and 14 nmol/L, respectively, inhibits the growth of various leukemic cell lines with IC50 of 1 nmol/L to 15 μmol/L, blocks the phosphorylation of BTK and PLCγ2, and inhibits secretion of TNF‐α, IL‐8 and IL‐6. It has favorable pharmacokinetic properties suitable for using as an oral anti‐cancer and anti‐arthritic drug. In accordance with the in‐vitro properties, it demonstrated robust efficacy in murine models of collagen‐induced arthritis (CIA) and streptococcal cell wall (SCW) induced arthritis. In both models, ZYBT1 alone could suppress the progression of the diseases. It also reduced the growth of TMD8 xenograft tumor. The results suggested that ZYBT1 has high potential for treating RA, and cancer.

Background Obesity, diabetes and dyslipidemica are the key pathogenic stimulus that enhances progression of Non-Alcoholic Fatty Liver Disease (NAFLD). Coagonist of Glucagon Like- Peptide-1 (GLP-1) Receptor (GLP-1R) and Glucagon Receptor (GCGR) are being evaluated for obesity and diabetes. GLP-1 analogs have shown to reverse diabetes and obesity. Glucagon treatment reduces lipids after acute and chronic treatment. Objective In this study, we have investigated the effect of co-agonist on the prevention of NAFLD induced by long-term feeding of High Fat Diet (HFD). Method We have used HFD to induce NAFLD after chronic feeding in mice. Co-agonist treatment (150 µg.kg-1, s.c.) was initiated with induction of HFD, which was continued for 40 weeks. Body weight, food intake, glucose homeostasis, lipid profile, inflammatory and fibrotic markers were assessed at the end of treatment. Results Co-agonist treatment prevented body weight gain, glucose intolerance and insulin resistance. Treatment with co-agonist reduced NEFA, increased FGF21 and adiponectin levels. Co-agonist increased glycerol release and energy expenditure, while decreased respiratory quotient. Co-agonist reduced lipids in circulation and liver. Expression of SREBP-1C, SCD-1, ACC and FAS were decreased, while ACOX1 and CPT1 were increased after co-agonist treatment. Inflammatory cytokine TNF-α and IL-6 in plasma and expression of MCP-1, TGF-s, MMP-9, TNF-α, TIMP-1, α-SMA, and COL1A1 were decreased after co-agonist treatment. Plasma transaminases, hepatic TBARS, hepatic hydroxyproline and relative liver weight were suppressed after co-agonist treatment. Fat accumulation, inflammation and fibrosis were reduced in histological assessment of liver in co-agonist treated animals. Conclusion Co-agonist prevented development of HFD-induced NAFLD by ameliorating obesity, diabetes, inflammation and fibrosis.

Nonalcoholic fatty liver disease (NAFLD) is often associated with obesity and type 2 diabetes. Coagonists of glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) are under clinical investigation for the treatment of obesity and type 2 diabetes. In this study, we have demonstrated the effect of a balanced coagonist in the treatment of NAFLD using mouse models. GLP-1R agonist exendin-4, glucagon, and coagonist (Aib2 C24 chimera2) were administered to C57BL6/J mice, in which NAFLD was induced by carbon tetrachloride (CCl4) treatment after high-fat diet (HFD) feeding, and choline-deficient, L-amino-acid-defined HFD (CDAHFD) feeding. Repeated dose administration of coagonist significantly attenuated liver inflammation and steatosis induced by acute and long-term treatment with CCl4 in HFD-fed mice. Coagonist markedly attenuated the CDAHFD-induced expression of TIMP-1, MMP-9, TNF-α, MCP-1, COL1A1, and α-SMA. It also inhibited progression of hepatic steatosis and fibrosis in mice. Exendin-4 was better than glucagon, but coagonist was most effective in reduction of hepatic inflammation as well as steatosis. Coagonist of GLP-1R and GCGR improved NAFLD in C57BL6/J mice. This effect is mediated by reduction in lipotoxicity and inflammation in liver.

Coagonists of Glucagon-like peptide-1 (GLP-1) and glucagon receptors are under clinical investigation for treatment of obesity associated with diabetes. In addition to their role in glucose homeostasis, GLP-1 and glucagon modulate lipid metabolism. In this study, we have investigated the role of central GLP-1 receptor (GLP-1R) and glucagon receptor (GCGR) activation in regulation of lipid metabolism in cholesterol-fed hamsters. Hamsters were treated with coagonist alone (0.3 μg) or in combination with either GLP-1R antagonist (0.15 μg) or GCGR antagonist (0.3 μg) for 4 weeks by intracerebroventricular route (icv). A pair-fed control to coagonist was included in the experiment. In a separate experiment, vagotomized hamsters were treated with coagonist (0.3 μg) for four weeks. At the end of the treatment, plasma and hepatic lipids, bile homeostasis, and hepatic gene expression were determined. Coagonist treatment caused a reduction in plasma and liver lipids, and reduced triglyceride absorption from intestine. Also, hepatic triglyceride secretion, bile flow, and biliary cholesterol excretion were increased by the coagonist treatment. Coagonist treatment exhibited increased energy expenditure and reduced the expression of SREBP-1C, HMG-CoA reductase, SCD-1, FAS and ACC in liver. Increase in the expression of LDLR, ACOX1, CPT-1, PPAR-α, CYP7A1, ABCA1 and ABCB11 was also observed in liver. The effect of coagonist on lipids was partially blocked by either GLP-1R or GCGR antagonist. Coadministration of GLP-1R antagonist blocked the effect of coagonist on bile flow, while effect of coagonist on biliary cholesterol was blocked by co-administration of GCGR antagonist. Coagonist did not affect lipid metabolism in vagotomized hamsters. It appears that central administration of coagonist reduces dyslipidemia by activation of GLP-1R and GCGR, independent of its anorectic effect.

Background and Purpose Dipeptidyl peptidase (DPP)-4 inhibitors increase levels of glucagon-like peptide-1 (GLP-1) and provide clinical benefit in the treatment of type 2 diabetes mellitus. As longer acting inhibitors have therapeutic advantages, we developed a novel DPP-4 inhibitor, ZY15557, that has a sustained action and long half-life. Experimental Approach We studied the potency, selectivity, efficacy and duration of action of ZY15557, in vitro, with assays of DPP-4 activity. In vivo, the pharmacodymamics and pharmacokinetics of ZY15557 were studied, using db/db mice and Zucker fatty rats, along with normal mice, rats, dogs and non-human primates. Key Results ZY15557 is a potent, competitive and long acting inhibitor of DPP-4 (Ki 5.53 nM; Koff 3.2 × 10−4·s−1, half-life 35.8 min). ZY15557 treatment inhibited DPP-4 activity, and enhanced active GLP-1 and insulin in mice and rats, providing dose-dependent anti-hyperglycaemic effects. Anti-hyperglycaemic effects were also observed in db/db mice and Zucker fatty rats. Following oral dosing, ZY15557 significantly inhibited plasma DPP-4 activity, determined ex vivo, in mice and rats for more than 48 h, and for up to 168 h in dogs and non-human primates. Allometric scaling predicts a half-life for ZY15557 in humans of up to 60 h. Conclusions and Implications ZY15557 is a potent, competitive and long acting DPP-4 inhibitor. ZY15557 showed similar DPP-4 inhibition across different species. ZY15557 showed excellent oral bioavailability in preclinical species. It showed a low plasma clearance (CL) and large volume of distribution (Vss) across species, resulting in an extended half-life.

ZYDPLA1 is a long acting enzyme dipeptidyl peptidase-4 (DPP-4) inhibitor. The comparative effect of DPP-4 inhibition after intravenous (IV) and oral administration of ZYDPLA1 in a rat model was evaluated to answer the question of route dependency and/or the need of high plasma levels of ZYDPLA1. The study was conducted using parallel design in male Wistar rats for IV/oral route (n=9 and 6, for IV and oral respectively). A single 30 mg/kg dose of ZYDPLA1 was administered. Plasma samples were analysed for ZYDPLA1 concentration and DPP-4 inhibition. Pharmacokinetic analysis was carried out to assess peak concentration, area under the concentration–time curve, total body clearance, elimination half-life, and mean residence time. The PK/PD correlation was performed using standard sigmoidal E max modelling to derive; maximum effect (E max ) and concentration to exert 50% Emax effect (EC 50 ). ZYDPLA1 showed rapid absorption, high volume of distribution, low clearance, and complete oral bioavailability. The E max derived after both routes and corresponding PK/PD profile showed comparable DDP-4 inhibition. The EC 50 for IV (0.021 µg/mL) was comparable to the oral route (0.019 µg/mL). ZYDPLA1 showed full DPP-4 inhibition without regard to the route of administration. Higher systemic peak levels showed no bearing on the DDP-4 inhibition.

Hexahydrocyclopentapyrrolone derivatives constitute an important class of bicycles, and it represents an essential pharmacophore for diversified pharmacological activities. A highly efficient process for the synthesis of tert-butyl(3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 1 has been developed. The improved process involves transformation of isoindole 4 to diacid 5, using an inexpensive KMnO4 mediated oxidative cleavage as a key step. The developed process was cost-effective, high yielding, kilogram scalable, and commercially viable for synthesis of 1.

Selective inhibition of janus kinase (JAK) has been identified as an important strategy for the treatment of autoimmune disorders. Optimization at the C2 and C4-positions of pyrimidine ring of Cerdulatinib led to the discovery of a potent and orally bioavailable 2,4-diaminopyrimidine-5-carboxamide based JAK3 selective inhibitor (11i). A cellular selectivity study further confirmed that 11i preferentially inhibits JAK3 over JAK1, in JAK/STAT signaling pathway. Compound 11i showed good anti-arthritic activity, which could be correlated with its improved oral bioavailability. In the repeat dose acute toxicity study, 11i showed no adverse changes related to gross pathology and clinical signs, indicating that the new class JAK3 selective inhibitor could be viable therapeutic option for the treatment of rheumatoid arthritis.

AIM To investigate the role of glucagon-like peptide-1 (GLP-1)/glucagon receptors coagonist on renal dysfunction associated with diabetes and obesity. METHODS Chronic high-fat diet fed C57BL/6J mice, streptozotocin-treated high-fat diet fed C57BL/6J mice and diabetic C57BLKS/J db/db mice were used as models of diabetes-induced renal dysfunction. The streptozotocin-treated high-fat diet fed mice and db/db mice were treated with the GLP-1 and glucagon receptors coagonist (Aib2 C24 Chimera2, 150 μg/kg, sc) for twelve weeks, while in chronic high-fat diet fed mice, coagonist (Aib2 C24 Chimera2, 150 μg/kg, sc) treatment was continued for forty weeks. Kidney function, histology, fibrosis, inflammation, and plasma biochemistry were assessed at the end of the treatment. RESULTS Coagonist treatment decreased body weight, plasma lipids, insulin resistance, creatinine, blood urea nitrogen, urinary albumin excretion rate and renal lipids. In kidney, expression of lipogenic genes (SREBP-1C, FAS, and SCD-1) was decreased, and expression of genes involved in β-oxidation (CPT-1 and PPAR-α) was increased due to coagonist treatment. In plasma, coagonist treatment increased adiponectin and FGF21 and decreased IL-6 and TNF-α. Coagonist treatment reduced expression of inflammatory (TNF-α, MCP-1, and MMP-9) and pro-fibrotic (TGF-β, COL1A1, and α-SMA) genes and also improved histological derangement in renal tissue. CONCLUSION Coagonist of GLP-1 and glucagon receptors alleviated diabetes and obesity-induced renal dysfunction by reducing glucose intolerance, obesity, and hyperlipidemia.

Hyperlipidemia is often associated with obesity and diabetes, and can lead to serious complications like atherosclerosis and fatty liver disease. Coagonist of GLP-1 and glucagon receptors is a therapy under clinical investigation for treatment of obesity and diabetes. In this study, we have characterized the mechanism of hypolipidemic effect of a balanced coagonist using high cholesterol-fed hamsters. Tyloxapol-induced hypertriglyceridemia, lipolysis in adipose tissue, and bile homeostasis were assessed after repeated dose treatment of the coagonist of GLP-1 and glucagon receptors (Aib2 C24 chimera 2, SC). Antagonists of GLP-1, glucagon, and FGF21 receptors were coadministered, and FGF21 sensitivity was determined in liver and adipose tissue. Repeated dose treatment of coagonist reduced cholesterol and increased FGF21 in blood and liver. Coagonist treatment reduced hepatic triglyceride secretion, increased lipolysis and reduced body weight. Antagonism of GLP-1 and glucagon receptors partially blocked the effect of the coagonist on lipid metabolism in circulation and liver, while FGF21 receptor antagonist completely abolished it. Glucagon and GLP-1 receptors antagonists blocked the action of coagonist on cholesterol excretion and bile flow in liver, but FGF21 antagonist was not effective. Treatment with the coagonist increased expression of FGF21, FGF21R and cofactor ßKlotho in liver and adipose. In conclusion, coagonist of GLP-1 and glucagon receptors improved lipid metabolism in liver of dyslipidemic hamsters. This effect is partially mediated by GLP-1 and glucagon receptors, and the improved FGF21 sensitivity could be the mechanism of hypolipidemic action of the coagonist of GLP-1/glucagon receptors.

Dyslipidemia enhances progression of atherosclerosis. Coagonist of GLP-1 and glucagon are under clinical investigation for the treatment of obesity and diabetes. Earlier, we have observed that coagonist reduced circulating and hepatic lipids, independent of its anorexic effects. Here, we investigated the role of coagonist of GLP-1 and glucagon receptors in complications of diet-induced dyslipidemia in hamsters and humanized double transgenic mice. Hamsters fed on high fat high cholesterol diet were treated for 8 weeks with coagonist of GLP-1 and glucagon receptors (75 and 150 μg/kg). Pair-fed control was maintained. Cholesterol fed transgenic mice overexpressing hApoB100 and hCETP with coagonist (300 μg/kg) for 4 weeks. After the completion of treatment, biochemical estimations were done. Coagonist treatment reduced triglycerides in plasma, liver and aorta, plasma cholesterol and hepatic triglyceride secretion rate. Expressions of HMG-CoA reductase and SBREBP-1C were reduced and expressions of LDLR, CYP7A1, ABCA1 and ABCB11 were increased in liver, due to coagonist treatment. Coagonist treatment increased bile flow rate and biliary cholesterol excretion. IL-6 and TNF-α were reduced in plasma and expression of TNF-α, MCP-1, MMP-9 and TIMP-1 decreased in liver. Treatment with coagonist reduced oxidative stress in liver and aorta. Energy expenditure was increased and respiratory quotient was reduced by coagonist treatment. These changes were correlated with reduced hepatic inflammation and lipids in liver and aorta in coagonist treated hamsters. Coagonist treatment also reduced lipids in cholesterol-fed transgenic mice. These changes were independent of glycaemia and anorexia observed after coagonist treatment. Long term treatment with coagonist of GLP-1 and glucagon receptor ameliorated diet-induced dyslipidemia and atherosclerosis by regulating bile homeostasis, liver inflammation and energy expenditure.

Increased lipid levels in blood contribute to increasing the risk of diabetic complications. Glucagon exerts lipid lowering effects in diabetic state. However, the mechanism behind the lipid reduction by glucagon independent of glucose homeostasis is not well understood. We assessed the actions of glucagon on lipid modulation in blood and markers in liver in hyperlipidemic hamsters and rats. Male Sprague Dawley rats and Golden Syrian hamsters on a hyperlipidemic diet for 2 weeks were administered a single dose of glucagon by subcutaneous (SC, 150 and 300 µg/kg) or intracerebroventricular (ICV, 15 and 30 µg/animal) route. Effect of acute treatment was observed on tyloxapol-induced hypertriglyceridemia, corn oil-induced post-prandial lipemia, and bile flow. A repeated dose treatment by subcutaneous (300 µg/kg) or intracerebroventricular (30 µg/animal) route was done for 2 weeks, following which circulating and hepatic lipids, hepatic markers of lipid metabolism and bile flow were assessed. Acute administration of glucagon (SC and ICV) decreased triglyceride absorption, hepatic triglyceride secretion rate and increased excretion of cholesterol in bile fluid in dose related manner. Repeated dose treatment reduced circulating and hepatic lipids and mainly LDL, and enhanced cholesterol excretion in bile. In liver, expression of HMG-CoA reductase was reduced while that of ABCA1 was increased after repeated treatment, whereas pair fed group did not show significant changes when compared to the control group. These findings demonstrate that central as well as peripheral glucagon effectively reduces hyperlipidemia in rat and hamster model, by modulating hepatic lipid metabolism.

Objective Dipeptidyl peptidase-4 (DPP-4) is responsible for degradation of glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP), the endogenous incretins that stimulate glucose-dependent insulin secretion. The objective was to evaluate preclinical profile of a novel DPP-4 inhibitor ZYDPLA1. Methods In vitro inhibition potency and selectivity were assessed using recombinant enzymes and/or plasma. In vivo efficacy was determined in oral glucose tolerance test or mixed meal tolerance test in C57BL/6J mice, db/db mice and Zucker fatty rats. Pharmacokinetics/pharmacodynamics was studied in mice, rats, dogs, and non-human primates. Results ZYDPLA1 is a potent, competitive and long acting inhibitor of DPP-4 (Ki 0.0027 μM; Koff 2.3 × 10–4 s–1). ZYDPLA1 was more than 7000-fold selective for recombinant DPP-4 relative to DPP-8 and DPP-9, and more than 60 000-fold selective relative to fibroblast activation protein (FAP) in vitro. DPP-4 inhibition was comparable across species. In vivo, oral ZYDPLA1 elevated circulating GLP-1 and insulin levels in mice and rats and showed dose-dependent anti-hyperglycemic effect. Anti-hyperglycemic effect was also observed in db/db mice and Zucker fatty rats. ZYDPLA1 showed low clearance, large volume of distribution, and a long half-life with excellent oral bioavailability in all species. It significantly inhibited plasma DPP-4 activity in mice and rats for more than 48 h, and for up to 168 h in dogs and non-human primates. Allometric scaling predicted a half-life in humans of 53 to 166 h. Conclusion ZYDPLA1 is a potent, selective, long-acting oral DPP-4 inhibitor with potential to become once-a-week therapy for treatment of type 2 diabetes mellitus. 摘要 目的： 二肽基肽酶-4（Dipeptidyl peptidase-4，DPP-4）负责胰高血糖素样肽-1（glucagon-like peptide 1，GLP-1）与胃抑制多肽（gastric inhibitory polypeptide，GIP）的降解，内源性的肠促胰岛素可以刺激葡萄糖依赖的胰岛素分泌。本研究的目的是评估一种新型DPP-4抑制剂：ZYDPLA1的临床前期特性。 方法： 在体外使用基因重组和/或血浆中的酶来评估它的抑制效力与选择性。在C57BL/6J小鼠、db/db小鼠以及Zucker肥胖大鼠中通过口服葡萄糖耐量试验或者混合餐耐量试验来测定其在体内的疗效。在小鼠、大鼠、狗以及非人类的灵长类动物中研究药物代谢动力学/药效动力学。 结果： ZYDPLA1是一种有效的、竞争性的长效DPP-4抑制剂（Ki 0.0027 μM；Koff 2.3 × 10−4s−1）。在体外ZYDPLA1对基因重组DPP-4的选择性相对于DPP-8与DPP-9来说高了7000倍，相对于成纤维细胞激活蛋白来说高了60000倍。对各物种DPP-4的抑制作用相似。在体内，小鼠与大鼠口服ZYDPLA1后可以升高循环中的GLP-1以及胰岛素水平，并且表现出了剂量依赖性的降糖作用。在db/db小鼠与Zucker肥胖大鼠中也能够观察到降糖作用。在所有的物种中ZYDPLA1都表现出了低清除率、巨大的分布容量、长半衰期以及极好的口服生物利用度。在小鼠与大鼠中它可以显著抑制血浆中的DPP-4活性长达48小时，而在狗与非人类的灵长类动物中更是长达168小时。按照这个比例预测其在人类中的半衰期为53-166小时。 结论： ZYDPLA1是一种有效的、选择性的长效口服DPP-4抑制剂，它有潜力成为每周一次给药的2型糖尿病治疗药物。

Cannabinoid 1 (CB1) receptor antagonists reduce body weight and improve insulin sensitivity. Preclinical data indicates that an acute dose of CB1 antagonist rimonabant causes an increase in blood glucose. A stable analog of glucagon-like peptide 1 (GLP-1), exendin-4 improves glucose-stimulated insulin secretion in pancreas, and reduces appetite through activation of GLP-1 receptors in the central nervous system and liver. We hypothesized that the insulin secretagogue effect of GLP-1 agonist exendin-4 may synergize with the insulin-sensitizing action of rimonabant. Intraperitoneal as well as intracerebroventricular administration of rimonabant increased serum glucose upon glucose challenge in overnight fasted, diet-induced obese C57 mice, with concomitant rise in serum glucagon levels. Exendin-4 reversed the acute hyperglycemia induced by rimonabant. The combination of exendin-4 and rimonabant showed an additive effect in the food intake, and sustained body weight reduction upon repeated dosing. The acute efficacy of both the compounds was additive for inducing nausea-like symptoms in conditioned aversion test in mice, whereas exendin-4 treatment antagonized the effect of rimonabant on forced swim test upon chronic dosing. Thus, the addition of exendin-4 to rimonabant produces greater reduction in food intake owing to increased aversion, but reduces the other central nervous system side effects of rimonabant. The hyperglucagonemia induced by rimonabant is partially responsible for enhancing the antiobesity effect of exendin-4.

A series of novel aminomethyl-piperidones were designed and evaluated as potential DPP-IV inhibitors. Optimized analogue 12v ((4S,5S)-5-(aminomethyl)-1-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-(2,5-difluorophenyl)piperidin-2-one) showed excellent in vitro potency and selectivity for DPP-IV over other serine proteases. The lead compound 12v showed potent and long acting antihyperglycemic effects (in vivo), along with improved pharmacokinetic profile.

Dual agonism of glucagon and glucagon-like peptide-1 (GLP-1) receptors reduce body weight without inducing hyperglycemia in rodents. However, the effect of a co-agonist on insulin sensitivity and lipid metabolism has not been thoroughly assessed. Diet-induced obese (DIO) mice received 0.5 mg·kg–1 of co-agonist or 2.5 mg·kg–1 of glucagon or 8 μg·kg–1 of exendin-4 by subcutaneous route, twice daily, for 28 days. A separate group of mice was pair-fed to the co-agonist-treated group for 28 days. Co-agonist treatment reduced food intake and reduced body weight up to 28 days. In addition, it reduced leptin levels and increased fibroblast growth factor 21 (FGF21) levels in plasma, when compared with control and pair-fed groups. Co-agonist treatment decreased triglyceride levels in serum and liver and reduced serum cholesterol, mainly due to reduction in low-density lipoprotein (LDL) cholesterol. These changes were not seen with pair-fed controls. Co-agonist treatment improved glucose tolerance and increased insulin sensitivity, as observed during glucose and insulin-tolerance test, hyperinsulinemic clamp, and reduced gluconeogenesis, as observed in pyruvate-tolerance test. The effects on insulin sensitivity and lipid levels are mostly independent of the food intake or body weight lowering effect of the co-agonist.

The glucokinase activators improve the fasting as well as postprandial glucose control and are important investigational drugs for the treatment of diabetes. However, recent studies have implicated that continuous activation of glucokinase with a small molecule activator can increase hepatic triglycerides and the long term glucose control is not achieved. In this study, we investigated the effect of combination of glucokinase activator (GKA, Piragliatin) with GLP-1 receptor agonist exendin-4 (Ex-4) in male db/db mice. Twelve weeks combination treatment in the db/db mice resulted in a significant decrease in body weight gain, food consumption, random glucose and %HbA1c. The decrease in serum glucose and %HbA1c in combination group was more profound and significantly different than that of individual treatment (GKA or Ex-4) group. GKA treatment increased hepatic triglycerides, whereas combination of Ex-4 with GKA attenuated hepatic steatosis. The combination of GKA with Ex-4 reduced the hepatic lipid accumulation, improved the insulin sensitivity, and reduced hepatic glucose production in db/db mice. Overall, our data indicate that combination of GKA and GLP-1 receptor agonist Ex-4 improves glucose homeostasis, shows antiobesity activity, without causing harmful side effects like fatty liver.

Combination with suitable pharmacological agents can improve the antiobesity and antidiabetic actions of glucagon like peptide-1 (GLP-1) based therapies. GLP-1 agonist exendin-4 may have insulin-independent effects on amelioration of insulin resistance and hepatic steatosis by virtue of its action on hepatic GLP-1 receptors, and these effects can be improved by combination with proton pump inhibitors. However, it was not assessed whether omeprazole can improve the peripheral actions of exendin-4 in the state of insulin deficiency.We investigated the effects of combination of omeprazole with GLP-1 agonist exendin-4 in multiple low-dose streptozotocin (STZ)-induced diabetes in C57BL/KsJ mice, a model of type 1 diabetes. Male diabetic mice were treated with exendin-4 and/or omeprazole for a period of 4 weeks.Omeprazole treatment had no significant effect on lowering the blood glucose levels of diabetic mice, when compared to control, although it improved the antihyperglycemic actions of exendin-4. Similarly, serum triglycerides and total cholesterols levels were significantly lower in the combination treated mice compared to either exendin-4 and omeprazole alone. In addition, the combination treatment significantly ameliorated lipid peroxidation and hepatic triglycerides in diabetic mice compared to either exendin-4 and omeprazole alone. The improvement in hepatic insulin sensitivity, as indicated by insulin tolerance test (ITT) and pyruvate tolerance test (IPPTT), was correlated with the expression of nuclear factor erythroid-related factor 2 (Nrf2) and insulin receptor substrate-1 (IRS-1) and the combination treatment significantly improved the insulin sensitivity in comparison to vehicle control.We conclude that combination with omeprazole improves the insulin sensitizing actions of GLP-1 therapy and these effects are partially mediated through the decrease in hepatic steatosis and improvement in antioxidant status in the liver.

A series of peptidomimetic containing bidentate pTyr mimetics (9a-w) are reported as potent and selective PTP1B inhibitors. Compounds (9p and 9q) showed excellent selectivity towards PTP1B over various PTPs, including TCPTP (in vitro), which confirms discovery of highly potent and selective PTP1B inhibitors.

Background: In addition to its glucoregulatory actions, exendin-4, a stable glucagon-like peptide-1 receptor agonist, exhibits protective effects in the pancreas and anti-obesity effects. Suitable combination treatment with other anti-obesity or pancreas protective agents would be an effective approach to optimize these additional effects. In the present study, we investigated the effects of the addition of omeprazole, a proton pump inhibitor, to exendin-4 in db/db mice, an experimental model of obesity and type 2 diabetes. Methods: The effects repeated dose treatment for 14 days with exendin-4 (8 μg/kg, s.c.) and omeprazole (30 mg/kg, s.c.) on glycemic control, food intake, and body weight were determined in obese and hyperglycemic db/db mice. The effects of these treatments on plasma gastrin, ghrelin, and leptin levels were determined, along with effects on nausea-like symptoms. The pancreatic effects of the repeated dose treatment were assessed by measuring %HbA1c in the circulation as well as pancreatic insulin and glucagon content and glucokinase activity. Results: Combination treatment resulted in significant decreases in plasma leptin and ghrelin levels after repeated dosing. Omeprazole improved the anorectic and body weight-lowering effects and reversed the inhibitory effect of exendin-4 on gastrin levels after repeated dose treatment. The 14-day combination treatment significantly reduced glucose excursion and improved insulin levels, with a concomitant decrease in %HbA1c levels. It also improved glucokinase activity and pancreatic insulin content, with a significant decrease in glucagon content. Conclusions: Combined treatment with omeprazole with exendin-4 reduces food intake and body weight gain, most likely through changes in plasma ghrelin and leptin levels, and improves pancreatic insulin and glucagon content by improving glucokinase activity.

A rapid and highly specific assay was developed and validated for the estimation of ZYDPLA1 in rat plasma using liquid chromatography coupled to tandem mass spectrometry with positive electrospray ionization. Method validation comprised of parameters such as specificity, matrix effect, precision, accuracy, recovery, stability, etc. The assay procedure involved a simple protein precipitation of ZYDPLA1 and alprazolam (internal standard) from rat plasma using acetonitrile. Chromatographic separation was achieved with a gradient mobile phase comprising: (A) 0.2% ammonia in purified water; (B) 0.1% formic acid in isopropyl alcohol/methanol (1: 1 v/v); and (C) acetonitrile at a flow rate of 1 mL/min on an ACE-5, C18 (4.6 × 50 mm) column with a run time of 5.5 min. The quantitation of ZYDPLA1 was achieved by the summation of four multiple reaction mode transitions (m/z 399.7 → 383.0, 399.7 → 276.10, 399.7 → 153.20 and 399.7 → 127.20), while that of the internal standard was by a single multiple reaction mode transition (m/z 309.10 → 281.00). The lower limit of quantitation achieved was 0.01 μg/mL and the method showed linearity from 0.01 to 25 μg/mL. The intra- and inter-day precision (%CV) of the quality control samples was within 8.81% and accuracy was ±10% of nominal values. This novel method was applied for evaluation of toxicokinetics of ZYDLA1 in rats.

Background: Glucagon-like peptide-1 (GLP-1) and its stable analogue exendin-4 maintain glucose homeostasis by modulating insulin secretion from pancreatic β-cells and controlling hepatic glucose output. Glucokinase (GK), by catalysing the first step in glycolysis, plays an important role in glucose-stimulated insulin secretion and hepatic glucose metabolism. In the present study, we investigated the effects of exendin-4 on GK in high fat-fed and alloxan-treated diabetic mice. Methods: The effects of alloxan (5, 10 and 20 μmol/L) on insulin release from isolated murine islets, as well as glycogen synthesis by isolated murine hepatocytes, were assessed. The effects of exendin-4 (10 nmol/kg, twice daily for 4 weeks) were assessed in high fat-fed, alloxan (50 mg/kg, i.v.)-treated C57 mice. Glucokinase activity was assessed in the same model. Results: Pretreatment with exendin-4 attenuated alloxan-induced decreases in insulin release and glycogen synthesis in islets and hepatocytes. The alloxan-induced decrease in the GK activity in islets and hepatocytes was also ameliorated by exendin-4 treatment. Pretreatment with the GLP-1 receptor antagonist exendin-9 (100 nmol/L) blocked the effects of exendin-4 on the liver and pancreas. Treatment of high-fat fed, alloxan-treated diabetic mice with exendin-4 (10 nmol/L, i.p.) reduced the severity of diabetic symptoms. Specifically, exendin-4 treatment reduced serum glucose by 50% and %HbA1c by 24% compared with control and significantly decreased HOMA-IR by 39% and increased HOMA-β by 150%. In addition, exendin-4 treatment significantly reduced body weight by 6.8% and serum triglycerides by 35%. Conclusions: The results indicate that glucose-stimulated insulin release and glycogen synthesis are decreased by alloxan due to reduced GK activity. These findings provide further insight into the mechanism by which exendin-4 regulates glucose homeostasis.

One-pot synthesis of 3,4-diaryl substituted 2(5H)-furanones was established and its commercial application has been demonstrated by accomplishing total synthesis of rofecoxib, under mild reaction conditions, with good yields and purity.

Series of benzyl-phenoxybenzyl amino-phenyl acid derivatives (8a–q) are reported as non-steroidal GR antagonist. Compound 8g showed excellent h-GR binding and potent antagonistic activity (in vitro). The lead compound 8g exhibited significant oral antidiabetic and antihyperlipidemic effects (in vivo), along with liver selectivity. These preliminary results confirm discovery of potent and liver selective passive GR antagonist for the treatment of T2DM.

Pyrrolidine based peptidomimetics are reported as potent and selective DPP-IV inhibitors for the treatment of T2DM. Compounds 16c and 16d showed excellent in vitro potency and selectivity towards DPP-IV and the lead compound 16c showed sustained antihyperglycemic effects, along with improved pharmacokinetic profile.

A novel series of pTyr mimetics containing triaryl-sulfonamide derivatives (5a–r) are reported as potent and selective PTP1B inhibitors. Some of the test compounds (5o and 5p) showed excellent selectivity towards PTP1B over various PTPs, including TCPTP (in vitro). The lead compound 5o showed potent antidiabetic activity (in vivo), along with improved pharmacokinetic profile. These preliminary results confirm discovery of highly potent and selective PTP1B inhibitors for the treatment of T2DM.

Exendin-4 is a stable peptide agonist of GLP-1 receptor that exhibits insulinotropic actions. Some in vivo studies indicated insulin-independent glucoregulatory actions of exendin-4. That finding prompted us to evaluate effects of exendin-4 on liver glucose metabolism. Acute and chronic treatment of exendin-4 resulted in increased hepatic glucokinase activity in db/db mice but not in lean C57 mice. The stimulatory effect of exendin-4 on glucokinase activity was abrogated by exendin 9-39, a GLP-1 antagonist. Exposure of hepatocytes isolated from db/db mice to exendin-4 elicited a rapid increase in cAMP, which was synergized by IBMX, an inhibitor of cAMP degradation. The GLP-1 antagonist, exendin 9-39, has abolished the cAMP generating effects of exendin-4 as well. Furthermore, chronic treatment of exendin-4 in streptozotocin-treated C57 mice resulted in restoration of hepatic glycogen, an indicator of improved glucose metabolism, without apparent changes in serum insulin levels. In conclusion, exendin-4 increased glucokinase enzyme protein and activity in liver via a mechanism parallel to and independent of insulin. Exendin-4-induced increase in hepatic glucokinase activity is more pronounced in the presence of hepatic insulin resistance. This beneficial effect of exendin-4 on liver glucokinase activity may be mediated by GLP-1 receptor.

The worldwide incidence of metabolic syndromes such as obesity and diabetes are increasing at an alarming rate. Patients that suffer from obesity-induced type 2 diabetes (informally known as diabesity) are at increased risk of cardiovascular disease; their numbers pose a significant economic burden on health services. Type 2 diabetes mellitus (T2DM) is clinically characterized by increased blood glucose levels, either due to defects in insulin secretion, insulin resistance, or both. Current treatments for diabetic patients include various oral antihyperglycemic agents; however, over a period of time nearly half of T2DM sufferers lose their response to these agents and thereby require insulin therapy. Except incretin therapies, most of the available anti-hyperglycemic agents including insulin promote weight gain, which further aggravates obesity-associated cardiovascular risk and insulin resistance. Thus, there is an urgent need to develop novel agents for glycemic control that can complement existing therapies and prevent the progression of secondary complications associated with diabesity. In recent years, development of protein tyrosine phosphatase 1B (PTP1B) inhibitors has been considered as one of the best validated biological targets for the treatment of T2DM. PTP1B acts as a negative regulator in insulin signaling pathways; it dephosphorylates key tyrosine residues within the regulatory domain of the b-subunit of the insulin receptor. Thus, the inhibition of PTP1B activity has the potential for enhancing insulin action by prolonging the phosphorylated state of the insulin receptor. Gene knockout studies in animals have also demonstrated that PTP1B / mice show increased insulin sensitivity and are resistant to diet-induced obesity. Over the past two decades, several structurally diverse small-molecule-based PTP1B inhibitors have been developed, including Ertiprotafib, which was discontinued in phase II clinical trials owing to lack of efficacy and dose-dependent side effects. Most of the initial PTP1B inhibitors, such as phosphonates, carboxylic acids, and difluoromethylphosphonates (DFMPs), were designed to bind to the active site (site 1/A) by mimicking the phosphotyrosine (pTyr) substrate. However, achieving PTP1B selectivity over closely associated PTPs (PTPa, LAR, CD45, VHR, SHP-1, SHP-2, and T-cell protein tyrosine phosphatase (TCPTP)) is one of the major challenges, as most of the closely associated PTPs, particularly TCPTP, share a high degree of primary sequence identity (92%) in the active site (pTyr binding pocket). Lack of oral bioavailability is another important issue in the development of potent and selective PTP1B inhibitors, as the majority of the active-site-directed PTP1B inhibitors exhibit limited cell permeability due to the presence of negatively charged polar groups. To address this problem, Zhang and colleagues identified an additional noncatalytic aryl phosphate binding site (site 2/B) proximal to the catalytic phosphate binding site. Site B of PTP1B differs from that of TCPTP by a few amino acids (F52Y and A27S) and thus offers an opportunity to improve selectivity over TCPTP. Consequently, dual-site inhibitors were designed to bind across both sites A and B, to achieve additive effects and thereby improve potency and selectivity toward PTP1B over closely associated PTPs. Based on this dual binding site concept, various DFMP-based PTP1B inhibitors such as arylketone 1, benzotriazoles 2a and 2b, and naphthyl derivative 3 were developed (Figure 1). The X-ray crystal structure of PTP1B in complex with compound 2b reveals that sites A and B each have a DFMP moiety anchored into it. The benzotriazole ring system also functions as an anchor and is located under the YRD loop, thereby rigidly locking the molecule into the active site and providing good selectivity for PTP1B over other PTPs. The fourth substituent (benzene ring) occupies a hydrophobic pocket. Altogether, this signifies that the presence of all four substituents oriented rigidly by the molecule’s stereocenter is essential for high potency and selectivity. Although results of oral bioavailability and in vivo antidiabetic activity assays for compound 2a have yet to be published, in vitro results show improved PTP1B inhibitory activity (IC50= 5 nm) and moderate selectivity (sevenfold) over TCPTP (IC50= 36 nm). The X-ray crystal structure of PTP1B in complex with compound 2a illustrates that a methoxy group aligns very closely (3.7 ) to the side chain of F52 (site B). Oral administration of compounds 1 and 3 demonstrated good antidiabetic activity (compound 3 : ED50=0.8 mgkg , p.o.) and oral bioavailability (compounds 1 and 3: F=13 and 24%, respectively) in different animal species, despite their moderate in vitro PTP1B inhibitory activity (IC50=120 nm) and poor selectivity [a] D. Patel, Dr. M. Jain, Dr. R. Bahekar, P. Jadav, B. Darji, Y. Siriki, Dr. D. Bandyopadhyay, Dr. A. Joharapurkar, S. Kshirsagar, H. Patel, M. Shaikh, Dr. K. V. V. M. Sairam, P. Patel Department of Medicinal Chemistry, New Drug Discovery Division Zydus Research Centre, Sarkhej-Bavla N.H. 8A Moraiya, Ahmedabad 382210 (India) Fax: (+91)2717-665-355 E-mail : rajeshbahekar@zyduscadila.com [b] D. Patel, Prof. S. R. Shah Department of Chemistry, Faculty of Science M.S. University of Baroda, Vadodara 390002 (India) Fax: (+91)0265-79-3693 E-mail : Shailesh-chem@msubaroda.ac.in [**] ZRC communication No. 378 (part of PhD thesis work of D.P.) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cmdc.201100077.

A novel series of thaizole and oxazole containing phenoxy acetic acid derivatives is reported as PPAR-pan agonists. Incorporation of structurally constrained oxime-ether based linker in the chemotype of a potent PPARδ selective agonist GW-501516 was adapted as designing strategy. In vitro, selected test compounds 12a, 12c, 17a and 18a showed PPAR-pan agonists activities and among these four compounds tested, 12a emerged as highly potent and efficacious compound, while 17a exhibited moderate and balanced PPAR-pan agonistic activity. In vivo, selected test compounds 12a and 17a exhibited significant anti-hyperglycemic and anti-hyperlipidemic activities in relevant animal models. These results support our hypothesis that the introduction of structurally constrained oxime-ether linker between lipophilic tail and acidic head plays an important role in modulating subtype selectivity and subsequently led to the discovery of potent PPAR-pan agonists.

Glucagon-like peptide-1 (GLP-1) receptor agonists modulate lipid metabolism, apart from controlling glucose homeostasis. We investigated the role of central GLP-1 receptor (GLP-1R) agonism in regulation of hepatic lipid metabolism in cholesterol-fed hamsters. Cholesterol-fed hamsters were treated by intracerebroventricular (i.c.v.) route with exendin-4, as acute or repeated dose regimen and compared with hamsters pair-fed to the exendin-treated hamsters and with hamsters co-treated with GLP-1 antagonist exendin-9. Effect of acute treatment was observed on food intake, tyloxapol-induced hypertriglyceridemia, and corn oil induced post prandial lipemia. Plasma and hepatic lipids and changes in the expression of hepatic genes involved in lipid metabolism were assessed after chronic administration. Acute, as well as repeated dose, treatment of exendin-4 showed significant changes in hepatic lipids, circulating fatty acids, triglycerides, LDL, and cholesterol. Expression of SREBP-1c was reduced while that of LDLR and CYP7A1 was increased after the repeated dose treatment, and there was no change in HMG CoA reductase. These changes were blocked by co-treatment of exendin-9, and not replicated by pair feeding to the significant extent. Central GLP-1 receptor activation showed profound effects on peripheral lipid metabolism, which were partially independent of its effect on food intake.

A new series of 3-(6-substituted-benzothiazol-2-yl)-6-phenyl-[1, 3]-oxazinane-2-thiones (4a-j) has been synthesised using an appropriate synthetic route (Scheme 1) and characterised by elemental analyses and spectral (IR, (1)HNMR, (13)C NMR, and EI MS) data. The anticonvulsant activity of all the title compounds (4a-j) was evaluated against Maximal Electroshock (MES) induced seizures and furthermore the most potent compounds were evaluated against subcutaneous pentylenetetrazole (sc PTZ) induced seizures model in mice. The neurotoxicity was assessed using the rotorod procedure. All the test compounds were administered intraperitoneally at various dose levels ranging from 30-200 mg/kg body wt and the median effective dose (ED(50)), median toxic dose (TD(50)), and protection index (PI) values were determined (Table 2). Among the compounds tested, the 3-(6-dimethylaminobenzothiazol-2-yl)-6-phenyl-[1, 3]-oxazinane-2-thiones (4j) was found to be the most potent (ED(50): 9.85 and 14.8 in MES model and 12 and 17 in scPTZ model at t = 0.5 h and 4 h, respectively, and TD(50) 42.8 and 44 at t = 0.5 h and 4 h, respectively, which has been found to be significant at p < 0.01 with respect to reference standard phenytoin) with protection index (PI) 4.85.

A series of tertiary amino compounds of type (I) is prepared as non-steroidal GR antagonists.

In addition to its glucoregulatory actions, exendin-4, a stable glucagon-like peptide-1 receptor agonist, exhibits protective effects in the pancreas and anti-obesity effects. Suitable combination treatment with other anti-obesity or pancreas protective agents would be an effective approach to optimize these additional effects. In the present study, we investigated the effects of the addition of omeprazole, a proton pump inhibitor, to exendin-4 in db/db mice, an experimental model of obesity and type 2 diabetes.The effects repeated dose treatment for 14 days with exendin-4 (8 μg/kg, s.c.) and omeprazole (30 mg/kg, s.c.) on glycemic control, food intake, and body weight were determined in obese and hyperglycemic db/db mice. The effects of these treatments on plasma gastrin, ghrelin, and leptin levels were determined, along with effects on nausea-like symptoms. The pancreatic effects of the repeated dose treatment were assessed by measuring %HbA1c in the circulation as well as pancreatic insulin and glucagon content and glucokinase activity.Combination treatment resulted in significant decreases in plasma leptin and ghrelin levels after repeated dosing. Omeprazole improved the anorectic and body weight-lowering effects and reversed the inhibitory effect of exendin-4 on gastrin levels after repeated dose treatment. The 14-day combination treatment significantly reduced glucose excursion and improved insulin levels, with a concomitant decrease in %HbA1c levels. It also improved glucokinase activity and pancreatic insulin content, with a significant decrease in glucagon content.Combined treatment with omeprazole with exendin-4 reduces food intake and body weight gain, most likely through changes in plasma ghrelin and leptin levels, and improves pancreatic insulin and glucagon content by improving glucokinase activity.

Glucagon-like peptide-1 (GLP-1) and its stable analogue exendin-4 maintain glucose homeostasis by modulating insulin secretion from pancreatic β-cells and controlling hepatic glucose output. Glucokinase (GK), by catalysing the first step in glycolysis, plays an important role in glucose-stimulated insulin secretion and hepatic glucose metabolism. In the present study, we investigated the effects of exendin-4 on GK in high fat-fed and alloxan-treated diabetic mice.The effects of alloxan (5, 10 and 20 μmol/L) on insulin release from isolated murine islets, as well as glycogen synthesis by isolated murine hepatocytes, were assessed. The effects of exendin-4 (10 nmol/kg, twice daily for 4 weeks) were assessed in high fat-fed, alloxan (50 mg/kg, i.v.)-treated C57 mice. Glucokinase activity was assessed in the same model.Pretreatment with exendin-4 attenuated alloxan-induced decreases in insulin release and glycogen synthesis in islets and hepatocytes. The alloxan-induced decrease in the GK activity in islets and hepatocytes was also ameliorated by exendin-4 treatment. Pretreatment with the GLP-1 receptor antagonist exendin-9 (100 nmol/L) blocked the effects of exendin-4 on the liver and pancreas. Treatment of high-fat fed, alloxan-treated diabetic mice with exendin-4 (10 nmol/L, i.p.) reduced the severity of diabetic symptoms. Specifically, exendin-4 treatment reduced serum glucose by 50% and %HbA1c by 24% compared with control and significantly decreased HOMA-IR by 39% and increased HOMA-β by 150%. In addition, exendin-4 treatment significantly reduced body weight by 6.8% and serum triglycerides by 35%.The results indicate that glucose-stimulated insulin release and glycogen synthesis are decreased by alloxan due to reduced GK activity. These findings provide further insight into the mechanism by which exendin-4 regulates glucose homeostasis.

Bioisosteric replacement of the rigid oxazole ring of a previously reported PPARα/γ dual agonist with a flexible lipophilic tail leads to a series of oxime containing benzyl dioxanecarboxylic acid derivatives.

A novel series of oxime containing benzyl-1,3-dioxane- r -2-carboxylic acid derivatives ( 6a – k ) were designed as selective PPAR α agonists, through bioisosteric modification in the lipophilic tail region of PPAR α / γ dual agonist. Some of the test compounds ( 6a , 6b , 6c and 6f ) showed high selectivity towards PPAR α over PPAR γ in vitro. Further, highly potent and selective PPAR α agonist 6c exhibited significant antihyperglycemic and antihyperlipidemic activity in vivo, along with its improved pharmacokinetic profile. Favorable in-silico interaction of 6c with PPAR α binding pocket correlate its in vitro selectivity profile toward PPAR α over PPAR γ . Together, these results confirm discovery of novel series of oxime based selective PPAR α agonists for the safe and effective treatment of various metabolic disorders.

(2000). A FACILE METHOD WITH IMPROVED YIELDS IN THE SYNTHESIS OF 6-ARYLPYRIDO[2′,3′:4,5]PYRIMIDO[1,6-a]BENZIMIDAZOLES. Organic Preparations and Procedures International: Vol. 32, No. 1, pp. 99-101.

(2000). A FACILE METHOD WITH IMPROVED YIELDS IN THE SYNTHESIS OF 6-ARYLPYRIDO[2′,3′:4,5]PYRIMIDO[1,6-a]BENZIMIDAZOLES. Organic Preparations and Procedures International: Vol. 32, No. 1, pp. 99-101.

beta-Carbolines stimulate insulin secretion in a glucose-dependent manner, probably by acting on I(3)-binding site. Knowing the in vitro glucose-dependent insulinotropic potential of beta-carbolines, in this project, three series of substituted-triaza-fluorene-6-carboxylic acids (5a-v, 6a-t, and 7a-t) were designed (analogs of beta-carboline) as a new class of insulinotropic agents. The in vitro glucose-dependent insulinotropic activities of test compounds were evaluated using RIN5F assay. Interestingly, with respect to the control, test compounds showed concentration-dependent insulin release, only in presence of glucose load (16.7 mmol). Some of the test compounds from each series were found to be equipotent to standard compound (Harmane), indicating that the pyridine ring systems of substituted-triaza-fluorenes act as bioisosteres of benzene ring in beta-carbolines.